Efficacy and safety of diazepam nasal spray in Japanese Pediatric patients with or at risk for status epilepticus: a phase 3, Multicenter, open-label clinical trial

Abstract

Objective

To evaluate the efficacy and safety of diazepam nasal spray (tradename: SPYDIA in Japan, VALTOCO® in the US) following single (Part 1) and multiple (Part 2) dose administrations in pediatric epilepsy patients.

Methods

Patients aged 6–17 years with status epilepticus (SE) or at risk for progression to SE despite stable antiseizure medication were eligible. In Part 1, a single intranasal dose (5, 10, or 15 mg) was administered immediately after the onset of a prespecified convulsive seizure. The primary endpoint was the responder rate (seizures ceasing within 10 min post-dose without recurrence for 30 min) in this part. In Part 2, multiple doses were administered for up to 24 weeks to assess efficacy and safety.

Results

From November 2022 and January 2024, 22 participants were enrolled in Part 1; 16 were treated. The responder rate was 62.5% (10/16; 95% CI, 35.4–84.8), with the lower CI limit exceeding the 30% threshold. In Part 2, 14 participants treated 91 seizures; 71.4% ceased within 10 min without recurrence for 12 h. Overall, 18 participants received diazepam nasal spray; 14 (77.8%) experienced treatment-emergent adverse events (TEAEs). No TEAEs led to discontinuation, and all treatment-related TEAEs were mild. Treatment satisfaction (“very” or “fairly” satisfied) was reported by 15/16 (93.8%) and 15/17 (88.2%) participants in Parts 1 and 2, respectively.

Conclusion

These findings support the favorable efficacy and safety profiles of diazepam nasal spray as a rescue therapy in pediatric patients with or at risk for SE.

Highlights

• •This study evaluated the efficacy and safety of diazepam nasal spray in pediatric patients with or at risk for status epilepticus.
• •Sixteen participants received a single dose for 16 seizures in Part 1; 14 received 91 doses for 91 seizures over 24 weeks in Part 2.
• •In Part 1, 62.5% of seizures ceased within 10 min after administration without recurrence for 30 min.
• •In Part 2, 71.4% of seizures ceased within 10 min after administration without recurrence for 12 h.
• •Treatment-emergent adverse events (TEAEs) occurred in 77.8% of participants; no TEAEs led to study discontinuation or death.

1. Introduction

Status epilepticus is considered the most severe form of seizure and requires immediate treatment [1]. Pediatric patients with seizure clusters, prolonged convulsive seizures, or a history of status epilepticus are at high risk of progression to status epilepticus [2], [3], [4], [5]. Current treatment guidelines recommend rescue medications for such patients [6], [7], [8], with benzodiazepines being the first-line therapy for early status epilepticus, seizure clusters, and prolonged convulsive seizures.

In Japan, rectal administration of diazepam, buccal administration of midazolam, and rectal administration of chloral hydrate are recommended for the acute treatment of early status epilepticus in pediatric patients in out-of-hospital settings [9]. However, rectal administration can be socially uncomfortable and associated with relatively slow onset of action because administered drug has to be absorbed via rectal mucosa [9]. In addition, buccal route of administration is limited by vomiting, hypersalivation, or uncontrollable swallowing [10], [11]. Therefore, a more convenient and socially acceptable route of administration is needed for pediatric patients.

Diazepam nasal spray is an intranasal formulation developed by Neurelis Inc. (San Diego, CA) [12]. In a phase 1 study in healthy adults, the exposure range of diazepam nasal spray at 15- and 20-mg doses was comparable to that of diazepam rectal gel [13], and systemic exposure increased with dose [14]. Furthermore, the results of an open-label study in patients with epilepsy aged 2–5 years showed that the pharmacokinetic and safety profiles of diazepam nasal spray in this age group were consistent with those in older patients [15]. As result, it is approved in the United States, Argentina, and China for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity in patients with epilepsy 2 years of age and older [12].

A recent Japanese phase 1 study assessed the pharmacokinetics and safety of a single intranasal dose of diazepam nasal spray in healthy participants [16]. In this study, the pharmacokinetic profile was consistent with those from the phase 1 studies conducted in the United States [13], [14]. The safety results were also consistent with those from the phase 3 open-label study conducted in the United States [17]. No safety issues specific to the Japanese population were identified.

Based on these findings, we conducted a phase 3, open-label study in Japan to evaluate the efficacy and safety of diazepam nasal spray in pediatric patients with or at risk for status epilepticus. This study consisted of two parts. In Part 1, a single dose of diazepam nasal spray was administered intranasally by caregivers if any of the following conditions were met: a convulsive seizure lasting ≥5 min; three or more repetitive convulsive seizures occurring within 1 h; or two or more convulsive seizures occurring without regained consciousness. The primary objective was to determine the proportion of seizures that ceased without recurrence after a single dose of diazepam nasal spray. In Part 2, multiple doses of diazepam nasal spray were administered immediately after the onsets of seizures over a 24-week period as needed, with continued assessment of efficacy and safety. The criteria for seizures requiring treatment and timing of diazepam administration were kept the same as those in Part 1.

2. Methods

2.1. Study design and oversight

This open-label clinical study was conducted at 12 institutions in Japan in accordance with the Declaration of Helsinki and the Good Clinical Practice. Institutional review board approval was obtained at each site. Written informed consent was obtained from all patients aged ≥16 years according to the Japanese reginal requirements. For patients aged <16 years, written consent was provided by caregivers, and assent was obtained from the patients, based on their levels of understanding. The study is registered with the Japan Registry of Clinical Trials (number: jRCT2031220265).

2.2. Study population

Japanese patients aged 6–17 years with a diagnosis of epilepsy were eligible if they had seizures despite a stable antiseizure medication regimen and were expected to require benzodiazepines for seizure control at least once every 6 months on average by investigators. Patients were expected to require benzodiazepines, if they had a history of: (1) convulsive seizures lasting ≥5 min, (2) convulsive seizures with a risk of progression to status epilepticus, or (3) status epilepticus. In this study, convulsive seizures were not restricted to tonic-clonic seizures and the types of convulsions were not recorded. Patients with non-convulsive seizures were not included.

Exclusion criteria included a history or current diagnosis of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease; known severe seasonal or non-seasonal allergies; or nasal polyps or any nasal passage abnormality that could interfere with nasal spray administration.

2.3. Treatment

In Part 1, a single intranasal dose (5, 10, or 15 mg) of diazepam nasal spray was administered by caregives immediately after they confirmed the first onset of: (1) a convulsive seizure lasting ≥5 min, (2) three or more convulsive seizures occurring within 1 h, or (3) two or more convulsive seizures occurring without regained consciousness. The dose of diazepam nasal spray was determined by age and body weight (Table S1). Although a maximum 20-mg dose was included in the protocol, it was not administered.

Part 2 began 1 week after the initial onset of the seizure treated in Part 1, provided the investigator deemed continued diazepam nasal spray use appropriate. The study period was extended to a maximum of 24 weeks. In Part 2, multiple doses of diazepam nasal spray were administered immediately after the onset of qualifying seizures. If seizures persisted, a second dose was permitted ≥4 h after the first dose; however, only two participants required a second dose. Thus, the results presented here reflect only the first dose of diazepam nasal spray.

Stable antiseizure medications were continued throughout the study. Rescue medication could be used at the onset of a convulsive seizure requiring emergency care. By contrast, concomitant use of the following medications was prohibited during the study: nasal decongestants, corticosteroid nasal sprays, diazepam-containing drugs (other than diazepam nasal spray), midazolam buccal solution, human immunodeficiency virus protease inhibitors, efavirenz, and cobicistat. Diazepam or midazolam could be administered after hospital transfer if required.

2.4. Outcome measures

In Part 1, participants were transported to a medical facility if a convulsive seizure persisted for >10 min after diazepam nasal spray administration or if diazepam nasal spray was given for a seizure lasting ≥5 min. Transportation was required even if the seizure ceased after arrangements were made. At the facility, treatment and examinations were performed based on each participant's condition. If not transported, participants were required to visit the study site within 24 h.

In Part 2, participants were transported if a seizure persisted for >10 min after diazepam nasal spray administration despite rescue medication or if no rescue medication was available for a prolonged seizure. Otherwise, participants visited the study sites at weeks 4, 8, 16, and 24.

In both parts, caregivers recorded seizure onset and drug administration times in a diary. Seizure cessation time and seizure status were assessed at 10 and 30 min, and at 1, 4, 6, 12, and 24 h post-administration. For hospitalized participants, investigators recorded the data. Treatment satisfaction was assessed at the end of each part. Investigators asked participants about treatment satisfaction using the following categories without definition: very satisfied, fairly satisfied, dissatisfied, and very dissatisfied. If participants could not respond, caregivers answered on their behalf. Specific questions were not used to assess treatment satisfaction.

In Part 1, the primary endpoint was the responder rate, defined as the percentage of seizures that ceased within 10 min after administration of diazepam nasal spray without recurrence for 30 min. In Part 2, this outcome measure was assessed as one of the secondary endpoints.

In both parts, secondary endpoints included: (1) proportion of seizures that ceased within 10 min after administration without recurrence at each time point post-administration (10 and 30 min, and 1, 4, 6, 12, and 24 h); (2) proportion of seizures that ceased within 10 min after administration; (3) time from administration to seizure cessation; and (4) treatment satisfaction.

Treatment-emergent adverse events (TEAEs) were monitored throughout both parts. A TEAE was defined as any adverse event occurring after diazepam nasal spray administration. Severity was graded per the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.03. Routine assessments included physical and neurological examinations, vital signs, 12‑lead electrocardiogram (ECG) recordings, laboratory tests, nasal evaluations (irritation and mucosal condition), sedation and pain assessments, and olfactory testing. These assessments were performed at screening, within 24 h post-dose, and the follow-up examination in Part 1 (Table S2–1). In Part 2, ECG was recorded in Week 24 and laboratory tests were performed in Weeks 8, 16, and 24 (Table S2–2). The other assessments were performed in Weeks 4, 8, 16, and 24. All assessments including ECG recording and laboratory tests were also to be performed at the end of the study if participants discontinued the study.

Table 1.

Baseline characteristics in the study popualtion in Parts 1 and 2.

	Part 1 (n = 16)	Part 2 (n = 17)	Part1 + Part2 (n = 18)
Sex, n (%)
Male	8 (50.0)	10 (58.8)	10 (55.6)
Female	8 (50.0)	7 (41.2)	8 (44.4)
Age (years), mean (SD)	11.0 (3.9)	11.2 (3.8)	10.9 (3.9)
Age categories
6 to 11 years	9 (56.3)	9 (52.9)	10 (55.6)
12 to 17 years	7 (43.8)	8 (47.1)	8 (44.4)
Body Weight (kg), mean (SD)	34.73 (14.13)	36.46 (14.86)	36.00 (14.55)
Duration of epilepsy (months), mean (SD)	127.1 (49.1)	129.4 (48.9)	126.7 (48.7)
Frequency of seizure (/week), median [min, max]	1.0[1, 24]	1.0[1, 24]	1.0[1, 24]
Dose of diazepam nasal spray, n (%)
5 mg	2 (12.5)	2 (11.8)	2 (11.1)
10 mg	9 (56.3)	9 (52.9)	10 (55.6)
15 mg	5 (31.3)	6 (35.3)	6 (33.3)
20 mg	–	–	0
Diagnosis of epilepsy, n (%)
Focal Epilepsy	7 (43.8)	7 (41.2)	8 (44.4)
Generalized Epilepsy	1 (6.3)	1 (5.9)	1 (5.6)
Combined Generalized and Focal Epilepsy	6 (37.5)	7 (41.2)	7 (38.9)
Unknown Epilepsy	2 (12.5)	2 (11.8)	2 (11.1)
History of seizure at the screening, n (%)
Convulsive seizure continued more than 5 min	15 (93.8)	16 (94.1)	17 (94.4)
Convlusive seizure with the potential to progression to status epilepticus	13 (81.3)	14 (82.4)	15 (83.3)
Status epilepticus	12 (75.0)	12 (70.6)	13 (72.2)
Classification of seizures at the start of study drug administration, n (%)
Single convulsive seizure lasting for 5 min or longer	4 (25.0)	9 (9.9)*	13 (12.1)
Convulsive seizure following three or more convulsive seizures within the preceding hour	12 (75.0)	81 (89.0)*	93 (86.9)
Convulsive seizure following two or more convulsions in succession with no recovery of consciousness	0	1 (1.1)*	1 (0.9)
Abbreviation: SD, standard deviation. *Number (%) of doses for the corresponding seizure.

Table 2.

Summary of TEAE (Part 1 + Part 2, N = 18).

	n (%)
TEAE	14 (77.8)
Serious TEAE	3 (16.7)
TEAE leading to study discontinuation	0
TEAE leading to death	0
TEAE related to the study drug	5 (27.8)
Serious TEAE related to the study drug	0
Frequently occurring TEAEs
Pyrexia	4 (22.2)
Influenza	4 (22.2)
Nasopharyngitis	3 (16.7)
Somnolence	3 (16.7)
Rhinalgia	3 (16.7)
Epilepsy	2 (11.1)
Treatment-related TEAEs
Somnolence	3 (16.7)
Anemia	1 (5.6)
Depressed level of consciousness	1 (5.6)
Oropharyngeal discomfort	1 (5.6)
Abbreviation: TEAE, treatment emergent adverse event.

Nasal irritation was evaluated using the following 6-point scale: Grade 0 = no sign of nasal irritation or mucosal erosion, Grade 1 A = focal nasal mucosal irritation or inflammation, Grade 1B = superficial mucosal erosion, Grade 2 = moderate mucosal erosion, Grade 3 = ulceration, and Grade 4 = septal perforation. Nasal mucosa was evaluated using the following 4-point scale for erythema, crust formation, edema, epistaxis, and secretions: Score 0 = no sign of mucosal abnormality (epistaxis, edema, discharge, erythema, crusting), Score 1 = mild mucosal abnormality, Score 2 = moderate mucosal abnormality, and Score 3 = severe mucosal abnormality. Participants and caregivers were also required to report any incident of nasal bleeding or inflammation that occurred between the time points for visiting the study site.

Sedation was evaluated using the following 6-point scale: 0 = alert, not drowsy, normal conversation; 1 = awake, talking, but somewhat drowsy; 2 = napping or sleeping, but easily awakened; 3 = sleeping, awakened only with loud voice or shaking; 4 = sleeping, very difficult to awaken, promptly returns to sleep; and 5 = sleeping, cannot awaken. Caregivers recorded the grade of sedation in a diary, and investigators confirmed the grade at each visit by reviewing the diary and examining the participant's condition. If participants were transported to a medical facility, investigators evaluated the grade after seizure cessation.

Acute pain in the nasal cavity after administration of diazepam nasal spray was evaluated using a visual analog scale consisting of a 100-mm horizontal line, where 0 mm indicated no pain and 100 mm indicated extreme pain. In the olfactory testing, the sense of smell was assessed using the Odor Stick Identification Test (Daiichi Yakuhin Sangyo Co., Ltd., Tokyo, Japan). Participants sniffed a given odor stick and identified the odor from the options. This was repeated for 12 different odors. The score was calculated with 1 point for the correct answer and 0 points for the others.

2.5. Statistical analysis

The target sample size was 15 participants, based on the enrollment rate in a recent Japanese phase 3 study in patients with status epilepticus (approximately one participant per site over 2 years) and an expected maximum of 15 study sites. Under this sample size, the probability that the lower limit of the 95% confidence interval (CI) for the responder rate would exceed the threshold (defined as 30%) was estimated to be 87%, if the responder rate would be 70% in this study. The threshold was determined according to the results of the randomized controlled trials using the similar endpoints [18], [19], [20]. In these trials, the responder rates in the rectal diazepam group ranged from 27% to 59%. Thus, we considered that the minimal clinically important rate would be 30%. The same threshold was also used in the phase 3 study of buccally administered midazolam conducted in Japan [21].

Baseline characteristics, efficacy outcomes (the primary and secondary endpoints), and treatment satisfaction were analyzed descriptively using the full analysis set, which included all participants who received or intended to receive the study drug and had relevant data. For the responder rate and time from administration to seizure cessation, the 95% CIs were also calculated. Thereafter, diazepam nasal spray was considered effective if the lower limit of the 95% CI for the responder rate in Part 1 exceeded 30%. Safety data were analyzed descriptively using the safety analysis set, comprising all participants who received diazepam nasal spray and had any safety datum during the study. Analyses were conducted using SAS® version 9.4 (SAS Institute, Cary, NC).

3. Results

3.1. Patient disposition

Between November 2, 2022, and January 5, 2024, 22 participants were enrolled in Part 1 (Fig. 1). Of these, 16 patients were treated with diazepam nasal spray, including two (12.5%) received 5 mg, nine (56.3%) received 10 mg, and five (31.3%) received 15 mg. These 16 participants were included in the analysis of baseline characteristics, efficacy outcomes, and treatment satisfaction in Part 1. The remaining six did not receive the study drug.

Fig. 1.

Participant flowchart.

Part 2 enrolled 18 participants (15 who previously received diazepam nasal spray in Part 1 and three who did not). Of these, 14 received diazepam nasal spray in Part 2, whereas three received it only in Part 1 and one did not receive it during the study. The reason for not receiving diazepam nasal spray was that participants did not have seizures. Consequently, 17 participants were included in the analysis of baseline characteristics and treatment satisfaction for Part 2, whereas 14 were included in the efficacy analysis.

The safety analysis included 18 participants who received diazepam nasal spray at least once throughout the study. All administrations occurred outside a hospital. The median (range) treatment duration was 116 (1–172) days.

3.2. Baseline characteristics

In Part 1, eight participants (50.0%) were female (Table 1). The mean (standard deviation [SD]) age was 11.0 (3.9) years, and mean (SD) body weight was 34.73 (14.13) kg. The mean (SD) epilepsy duration was 127.1 (49.1) months. Focal epilepsy was the most common type (seven participants, 43.8%), followed by combined generalized and focal epilepsy (six participants, 37.5%). Median (range) seizure frequency was 1 (1–24) per month. The baseline characteristics of 17 patients in Part 2 were similar to those of 16 patients in Part 1. All 18 participants used at least one concomitant medication. The most common medications were sodium valproate (nine participants, 50.0%) and clobazam (eight participants, 44.4%).

3.3. Efficacy

In Part 1, 16 participants received diazepam nasal spray for 16 seizures, and the responder rate was 62.5% (10 of 16 seizures; 95% CI, 35.4–84.8) (Fig. 2). The lower limit of the 95% CI exceeded the predefined threshold of 30%. In Part 2, 14 participants received a total of 96 doses for 91 seizures, with the response rate of 80.2% (73/91 seizures). Responder rates by seizure type were similar across both parts (Fig. S1).

Fig. 2.

Responder rates in Parts 1 and 2.

A responder rate was defined as the percentage of seizures that ceased within 10 min after administration of diazepam nasal spray without recurrence for 30 min. In Part 1, 16 participants received diazepam Nasal Spray for 16 seizures, and the responder rate was 62.5% (10 of 16 seizures; 95% confidence interval [CI], 35.4–84.8). In Part 2, 14 participants received a total of 91 doses for 91 seizures, with the responder rate of 80.2% (73 of 91 seizures; 95% CI, 70.6–87.8).

Fig. 3 displays the seizure cessation rates without recurrence at 10 and 30 min and at 1, 4, 6, 12, and 24 h after administration. The seizure cessation rates without recurrence over 12 h was 50.0% in Part 1 and 71.4% in Part 2; over 24 h, 43.8% in Part 1 and 67.0% in Part 2.

Fig. 3.

Proportion of seizures that ceased within 10 min after administration ofdiazepam nasal spray without recurrence for 10 and 30 min and for 1, 4, 6, 12, and 24 h after administration of diazepam nasal spray.

The percentage of seizures that ceased within 10 min after diazepam administration was 93.8% (15/16 seizures) in Part 1 and 98.9% (90/91 seizures) in Part 2. The median time from diazepam administration to seizure cessation was 1.5 min (95% CI, 1.0–7.0) in Part 1 and 1.0 min (95% CI, 1.0–2.0) in Part 2.

Results of the primary and secondary oucomes were descriptively compared between participants aged <12 years and those aged ≥12 years (Table S3). Although the sample size was limited, efficacy results were similar between the subgroups divided by age.

3.4. Safety

Across the study, 14 participants (77.8%) reported at least one TEAE (Table 2). Serious TEAEs occurred in three participants (16.7%): one had epilepsy in Part 1, one had influenza and epilepsy in Part 2, and one had status epilepticus in Part 2. None were related to diazepam nasal spray. The incidence of serious TEAEs was comparable between participants aged <12 years and those aged ≥12 years (Table S3). No TEAEs led to study discontinuation or death. Furthermore, no TEAEs indicated respiratory depression. Treatment-related TEAEs were reported in five participants (27.8%). The most common event was somnolence (three participants, 16.7%), followed by anemia, depressed level of consciousness, and oropharyngeal discomfort (one participant, 5.6%, for each). Although somnolence was considered treatment related by investigators, the relationship between the onset of somnolence and seizure cessation was not recorded. Thus, it was difficult to determine whether somnolence was due to the post-ictal state or the effects of the medication. All treatment-related TEAEs were mild (Grade 1).

No clinically significant abnormalities were found in laboratory tests, vital signs, physical examinations, or 12‑lead ECG findings. Although one participant (6.3%) in Part 1 had infectious symptoms in the physical examamination performed within 24 h post-dose, the symptoms were related to beta hemolytic streptococcal infection that had occurred before the administration of diazepam nasal spray. Nasal evaluations, sedation and pain assessments, and olfactory testing also revealed no significant findings. Olfaction scores were within the range of 3–10. In the neurological examination, one participant (6.3%) showed abnormal findings within 24 h post-dose (i.e., after the onset of seizure) in Part 1. The category was state of consciousness, and the partipant was found dazed.

3.5. Treatment satisfaction

In Part 1, all 16 participants responded to the treatment satisfaction question (Fig. 4). Of these, eight participants (50.0%) answered “very satisfied” and seven (43.8%) answered “fairly satisfied.” Only one participant answered “dissatisfied.” As a result, the proportion of participants who answered “very satisfied” or “fairly satisfied” was 93.8% (15/16). In Part 2, 15 participants responded; two did not. The proportion of participants reporting “very satisfied” or “fairly satisfied” was 88.2% (15/17).

Fig. 4.

Treatment satisfaction responses as reported by participants or caregivers. Investigators asked participants about treatment satisfaction at the end of each part using the following categories without definition: very satisfied, fairly satisfied, dissatisfied, and very dissatisfied. If participants could not respond, caregivers answered on their behalf.

4. Discussion

In Part 1 of this study, 62.5% of participants achieved seizure cessation within 10 min after administration of diazepam nasal spray, with no recurrence for 30 min. The lower bound of the 95% CI surpassed the prespecified efficacy threshold of 30%. Yoshinaga et al. used the same primary endpoint in an open-label study of buccally administered midazolam [21]. In this study, they defined 30% as the minimum clinically meaningful threshold. Accordingly, our findings support the efficacy of diazepam nasal spray for seizure resolution. This effect did not differ by seizure type.

In Part 2, 14 participants received diazepam nasal spray for 91 seizures, and 71.4% of seizures ceased within 10 min post-dose without recurrence for 12 h. In a randomized placebo-controlled trial of diazepam rectal gel in adults, 71% (22/31) of participants in the diazepam group and 28% (11/39) in the placebo group remained seizure-free over 12 h [22]. Furthermore, an exploratory analysis from a long-term, open-label safety study showed that the use of second dose of diazepam nasal spray was consistently low [23]. In this analysis including 163 partipnats (mean age 23.1 years [range: 6–65]), the proportion of seizure clusters treated with a second dose of diazepam nasal spray was less than 4% across 24 h. Thus, our findings suggest diazepam nasal spray produces a similarly sustained effect in pediatric patients.

The median time from diazepam nasal spray administration to seizure cessation was under 2 min in both parts. According to expert consensus recommendations for outpatient management of prolonged seizures and seizure clusters, an ideal rescue medication should act within 2 min [24]. However, a cross-sectional survey on pediatric seizure management in out-of-hospital settings reported an average time to seizure resolution exceeding 10 min, with caregivers expressing the need for faster-acting options [25]. Our results therefore highlight the favorable efficacy profile of diazepam nasal spray as a rescue medication. Additionally, a phase 3 survey showed that nearly 60% of patients and caregivers reported returning to their baseline state or daily activities within 1 h of administration [26]. This underscores the practical benefit of rapid-onset treatment in daily life.

Currently, benzodiazepines are recommended for the first-line treatment of early status epilepticus and seizures with high risk for progression to status epilepticus [27], [28]. In fact, an exploratory analysis using data of the long-term study in patients with refractory epilepsy and frequent seizure clusters (mean age 23.1 years) indicated that early treatment with diazepam nasal spray led to faster seizure resolution [29]. Our results revealed that early treatment with diazepam nasal spray was also effective for pediatric patients aged 6–17 years. Moreover, the pharmacokinetic profile of diazepam nasal spray in pediatric patients aged 2–5 years was similar with that in older patients [15]. Considering these results, diazepam nasal spray may be considered a valuable rescue treatment option for patients aged ≥2 years.

Diazepam nasal spray was well tolerated. No TEAEs led to study discontinuation or suggested respiratory depression. Five patients experienced treatment-related TEAEs, all classified as Grade 1. Although the mean treatment duration was approximately 4 months, long-term safety data are available from an open-label study involving patients aged 6–65 years with seizure clusters despite stable antiseizure regimens [17]. In that study, diazepam nasal spray was administered 4390 times for 3853 seizure clusters, with no serious treatment-related TEAEs. Subgroup analysis further confirmed a favorable safety profile in patients aged 6–17 years [30]. Diazepam nasal spray also demonstrated favorable safety profile in an open-label study that enrolled patients aged 2–5 years [15]. The safety results in this study were consistent with those in older patients without any unexpected adverse events in this age group.

Regarding treatment satisfaction, approximately 90% of participants reported being satisfied with diazepam nasal spray. This likely reflects its efficacy and safety. No issues were reported with its use in out-of-hospital settings. An ideal rescue medication should be easy to administer, act quickly, have a sustained effect, and cause minimal adverse effects. Although we did not directly compare ease of use between formulations, a recent narrative review indicated that patients and caregivers prefer nasal over rectal administration [31]. The buccal route of administration is limited by factors such as jaw clenching, hypersalivation, and involuntary swallowing, which contribute to inconsistent pharmacodynamics [32]. The intranasal route may therefore offer advantages over rectal or buccal administration.

4.1. Limitations

This study employed an open-label design without a comparator group. Thus, the responder rate or the proportion of seizures that ceased without reccurence for the prespecified periods might be overestimated. However, the efficacy of diazepam rectal gel has been established in the randomized, placebo-controlled trials [33], [34]. Given the similar pharmacokinetic profiles of the formulations, diazepam nasal spray appears to offer comparable effectiveness. In addition, the timing of administration and the assessments of seizure onset and termination were based on caregiver judgment, which may have introduced inter-rater variability. However, we consider that intra-rater variability might be small because the caregiver-participant combination was almost consistent within each family. Other limitations include the exclusion of adult patients, limited treatment period, and a small sample size. The efficacy and long-term safety of diazepam nasal spray in various Japanese patients should be evaluated in further studies including post-marketing surveillance.

5. Conclusion

In this open-label clinical study of patients aged 6–17 years with seizures despite stable antiseizure regimens, 62.5% of participants in Part 1 achieved seizure cessation within 10 min of diazepam nasal spray administration, with no recurrence over 30 min. The lower bound of the 95% CI exceeded the 30% efficacy threshold. In Part 2, 71.4% of seizures ceased within 10 min post-dose without recurrence for 12 h. In both parts, the median time from administration to seizure cessation was under 2 min. Diazepam nasal spray was well tolerated, with no study discontinuations due to TEAEs, and only Grade 1 treatment-related events were reported. No issues were noted with its use in out-of-hospital settings. These findings suggest that diazepam nasal spray may be an effective and generally well-tolerated rescue therapy for pediatric patients with epilepsy experiencing prolonged seizures or at risk for status epilepticus in out-of-hospital settings.

The following are the supplementary data related to this article.

CRediT authorship contribution statement

Eiji Nakagawa: Writing – review & editing, Resources, Methodology, Investigation, Conceptualization. Jun Tohyama: Writing – review & editing, Resources, Methodology, Investigation, Conceptualization. Ryutaro Kira: Writing – review & editing, Resources, Investigation. Mitsugu Uematsu: Writing – original draft, Resources, Investigation. Shin Okazaki: Writing – review & editing, Resources, Investigation. Hideaki Shiraishi: Writing – review & editing, Resources, Investigation. Kazuhiro Muramatsu: Writing – review & editing, Resources, Investigation. Kazuya Itomi: Writing – review & editing, Resources, Investigation. Junichi Onuma: Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Formal analysis, Data curation, Conceptualization. Shinichiro Takeuchi: Writing – review & editing, Methodology, Conceptualization. Kikuo Tsukahara: Writing – review & editing, Methodology, Funding acquisition, Conceptualization. Katsumi Imai: Writing – review & editing, Resources, Methodology, Investigation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.